Clear evidence exists that CD8 T cell responses to the circumsporozoite protein of the rodent Plasmodia (P. berghei or P. yoelii) can stop the infection at the liver stage in BALB/c mice, thus preventing the symptomatic blood stage of malaria. Our laboratory has spent considerable effort over the last decade developing approaches to stimulate and analyze CD8 T cell memory responses after infection and vaccination. Our initial goal in entering the malaria field was not to develop a vaccine, but instead to devise a model system that would permit us to study the immunological mechanisms resulting in protective immunity mediated by memory CD8 T cells. As shown in the preliminary data of this proposal and a recent publication in PNAS1, our laboratory has developed an immunization strategy to generate P. berghei circumsporozoite (CS)-epitope- specific memory CD8 T cells that provides essentially life-long protection of BALB/c mice against multiple challenges with Plasmodium sporozoites (spz). We used this model to determine that CS-specific memory CD8 T cells exceeding a large (>20% of CD8 T cells), but definable frequency (>1% of all PBL) were required for sterilizing immunity. Our long-term goal is to exploit this quantitative model system to understand the basic immunological mechanisms that result in memory CD8 T cell-mediated protective immunity against the liver stage of Plasmodium infection, information that could be critical for the rational design of efficacious vaccines against malaria. We will address this long-term goal through the following specific aims: Aim 1. Determine if the large threshold of CS-specific CD8 T cells required for protection of BALB/c mice against P. berghei infection is generalizable to other Plasmodium species/epitopes or other mouse strains. Aim 2. Determine how CS-specific memory CD8 T cells protect against liver stage Plasmodium infection. Aim 3. Determine if and how recruitment of other immune effector cells and pathways reduces the threshold required for CS-specific CD8 T cells to provide sterilizing immunity to Plasmodium challenge. Aim 4. Determine if recurring infections with unrelated pathogens result in attrition of CS-specific memory CD8 T cells and compromise sterilizing immunity.